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www.aging-us.com AGING 2020, Vol. 12, No. 11

Research Paper

How non-drug interventions affect the quality of life of patients suffering from progressive cognitive decline and their main caregiver

Benedetta Leidi-Maimone1,*, Marie-Laure Notter-Bielser1,*, Marie-Hélène Laouadi1, Sarah Perrin1,2, Hélène Métraux3, Daniel Damian1, Camille F. Chavan4, Mélanie Nsir5, Gwendoline Cibelli6, Marie-Jo Tâche7, Marie-Louise Montandon8,9, Joseph Ghika10, Jean-François Démonet1,9, Anne-Véronique Dürst11, Andrea Brioschi Guevara1,9 1Leenaards Memory Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland 2Service of Old Age Psychiatry, Department of Psychiatry (SUPAA), Lausanne University Hospital (CHUV), Lausanne, Switzerland 3Vaud Association for Help and Home Care (AVASAD, Association Vaudoise d’Aide et de Soins à Domicile), Lausanne, Switzerland 4Memory Center of the Neuropsychology and Aphasiology Unit, Fribourg Hospital (HFR), Fribourg, Switzerland 5Nord Broye Memory Center, Montagny-près-Yverdon, Switzerland 6East Memory Center of Canton Vaud, Rennaz, Switzerland 7La Côte Memory Center, Rolle, Switzerland 8Memory Center of the Geneva University Hospitals (HUG), Geneva, Switzerland 9CU ROMENS, Switzerland 10Valais Hospital Memory Center, Sierre, Switzerland 11Service of Geriatric Medicine and Geriatric Rehabilitation, Lausanne University Hospital (CHUV), Lausanne, Switzerland *Equal contribution

Correspondence to: Andrea Brioschi Guevara; email: andrea.brioschi-guevara@chuv.ch Keywords: non-drug intervention, quality of life, MCI, caregiver, dementia Received: December 17, 2019 Accepted: April 27, 2020 Published: June 9, 2020

Copyright: Leidi-Maimone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Background: In the absence of cure for age-related neurodegenerative diseases, non-drug interventions (NDIs) represent useful options. Quality of life (QOL) is a multidimensional concept progressively affected by cognitive decline. How single or multiple NDIs impact QOL is unknown. Results: We found no significant effect of multiple over single NDI on QOL. Socio-demographic variables influenced patients’ (age, gender, caregivers’ occupational status, management of patients’ financial affairs) and caregivers’ (gender, occupational status, patients’ severity of cognitive decline) QOL. When dyads interrupted interventions after 6 months, their QOL was lower and caregivers’ anxiety, depression and physical symptoms were higher at the end of the study. Conclusions: While the type and number of interventions do not appear to be critical, the continuity of adapted interventions in the long-term might be important for maintaining QOL of patients and caregivers. Methods: This is a multicenter (7 Swiss Memory Clinics), quasi-experimental, one-year follow-up study including 148 subjects (mild cognitive impairment or mild dementia patients and their caregivers). Primary outcome was the effect of multiple vs single NDIs on QOL. Secondary outcome included NDIs effect on patients’ cognitive impairment and functional autonomy, caregivers’ burden, severity of patients’ neuropsychiatric symptoms and dyads’ anxiety and depression.

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INTRODUCTION

The ageing process occurring worldwide is associated

with an increasing number of age-related diseases, such

as pathologies slowing down cognition. Severity of

cognitive dysfunction range from mild cognitive

impairment (MCI) to dementia. In 2017, the World

Health Organization (WHO) reported nearly 50 millions

of people suffering from dementia worldwide, a number

expected to triple by 2050 [1], leading to important

social and financial adversities.

Although new hopes exist with disease-modifying drugs,

effective curative therapies for Alzheimer’s disease

(AD) remain to be found. According to international

health leaders, curative drug treatment for age-related

neurodegenerative diseases will not be available before

2025 [2]. Whatever these drug-related possible

advances, the treatment of complex and chronic diseases

involves in general the combination of different

therapeutic approaches such as pharmacological and

non-pharmacological care.

The purpose of non-drug intervention (NDI) is to

maintain patients’ cognitive function and functional

autonomy in activities of daily living, as well as to

improve behavioral and psychological symptoms

(BPSD) that frequently flank memory disorders, while

enhancing individuals’ quality of life (QOL). In

particular, NDI are considered as first-line treatment for

the management of BPSD [3], such as anxiety, agitation

or apathy, which are experienced by nearly three-fourths

of patients with dementia [4, 5]. Importantly, NDIs may

also delay patients’ institutionalization and relieve

caregivers’ burden [6]. Indeed, as 60% of the patients

suffering from dementia live at home and are being

cared for by a family member [1], reducing caregivers’

mental and physical exhaustion is an important goal of

NDIs in order to preserve their QOL and general health.

Non-drug interventions are therefore receiving increased

attention as interesting approaches with limited adverse

effects for patients with evolutive cognitive diseases and

their related caregivers.

The WHO defines QOL as “an individual’s perception

of their position in life in the context of the culture and

value systems in which they live and in relation to their

goals, expectations, standards and concerns” [7]. Quality

of life is a multidimensional concept directly influenced

by physical and psychological state, independence level,

personal benefits, social relationships and relationships

to salient features of the environment. Progressive

cognitive decline slowly affects one or many of these

dimensions in both patient and caregiver, the former

becoming a source of physical, psychological, social

and/or financial burden for the latter [8].

The relationship between QOL and cognitive

impairment is not straightforward. Amer et al. [9] stated

that QOL is lower in cognitively impaired individuals

than in those with normal cognition, and Pan et al. [10]

showed that the negative influence of cognitive decline

on health-related QOL in older adults increases with

cognitive dysfunction severity. However, others failed to

find an association between QOL and dementia extent

[11, 12]. A study by Boström et al. [13] compared

Lewy’s bodies dementia (LBD) patients with AD

patients and showed the firsts to have a significantly

lower QOL than the latter’s, possibly because of the

presence of greater behavioral symptoms in LBD than

AD (e.g. apathy). Along with this view, other authors

have associated BPSD with both patients’ [11] and

caregivers’ [14] negative scores of QOL. In addition to

cognition, other factors have been associated to QOL.

For instance, patients’ comorbidity has been inversely

related to their own QOL [12, 15] and caregiver’s

burden is a predictor of lower QOL in both patients and

caregivers [16]. Sex, age and level of education show

inconsistent influence on QOL [17].

In response to the increasing number of patients

suffering from dementia and of caregivers burdened by

the disease, national and international strategies (WHO

“global action plan on the public health response to

dementia” [18]) are developed in order to improve

patients’ as well as their caregivers’ and families’ life. In

Switzerland, a network of Memory Clinics has been

created with the aim to establish a universal set of

procedures and standards for clinical evaluation, patient

early diagnostic of cognitive decline, possible referral

and follow-up. Following a multidisciplinary assessment

of the patient by neurologists, psychiatrists, geriatricians,

neuropsychologists, nurses and social assistants, the

patient and his family receive the diagnosis and a

therapeutic and care plan is discussed. In particular,

Memory Clinics can propose diverse and personalized

NDIs to overcome age-related and progressive cognitive

decline in patients and to assist caregivers. Personalized

NDIs are tailored according to patient’s underlying

disease, preferences for specific activities or interests

and the extent of caregiver’s burden, and they include a

variety of disciplines in order to take advantage of

patients’ preserved functions favoring brain plasticity to

enlarge cognitive reserve and thus slow down cognitive

decline [19].

WHO guidelines for cognitive decline risk reduction

in mild cognitive impaired (MCI) adults endorse

the importance of NDIs [20]. The recommended

NDIs include physical activity and cognitive

interventions. Furthermore, psychological interventions

are recommended for the management of depression, a

symptom affecting as many as half of AD patients [21].

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Similarly, systematic reviews have identified a variety

of non-pharmacological treatments as useful in the

short-management of apathy and anxiety in mild to

moderate dementia patients [22–24]. In general,

behavioral management techniques have been shown to

improve depression, anxiety and agitation in dementia

[25]. A recent study on MCI patients showed a

significant effect of a 2-months cognitive intervention

(focused on memory and attentional control) on

memory scores and strategies implementation in

everyday activities, with a maintain of these effects 6

months after intervention [26]. Similarly, occupational

therapy improved mild-to-moderate dementia patients’

and their caregivers’ QOL, health status and mood after

10 sessions over 5 weeks [27]. Non-drug interventions

also play an important role when tailored to the

caregivers’ need. For example, a review on NDIs for

caregivers of AD patients report interventions based on

psychosocial training and education (e.g., information

about the disease, skills training for BPSD management,

counselling and support) as to be effective at reducing

caregiver burden [28].

However, in a large French randomized-controlled-trial

[29], group cognitive training, group reminiscence

therapy and individualized cognitively rehabilitation did

not show any benefit on cognitive decline, functional

abilities in daily life activities, QOL, and caregiver’s

burden when compared with usual care.

A meta-analysis on the effects of NDIs in dementia

suggests that a combination of multiple NDIs is more

effective than a single intervention [30].

With the intent to observe in a real-life setting the

interventions proposed by Memory Clinics in the French

part of Switzerland, we conducted an observational

quasi-experimental longitudinal study “INDID-MCI-

QOL” (Impact of non-drug intervention in dementia and

mild cognitive impairment – Quality of life). We aimed

at investigating the effect of personalized NDIs on the

QOL of patients suffering from MCI or mild dementia

and their main caregivers. In the present study we

arbitrarily subdivided NDIs into five categories:

functional, cognitive, medico-social, psychology and

socialization. Our main hypothesis was that a

combination of multiple and personalized NDIs (i.e.,

experimental condition) would have a bigger impact on

QOL than a single intervention (i.e., control condition).

Indeed, acting on a single dimension of QOL is often

insufficient to preserve QOL. We believe that a

combination of multiple NDIs responding to the need of

the dyad patient-caregiver is essential to target the

different dimensions of the complex QOL concept.

Secondary outcomes included the exploration of the

effect of interventions on other measures (i.e. patients’

cognitive impairment, physical frailty, functional

autonomy and chronic medical illness burden;

caregivers’ physical symptoms and burden; patient’s

neuropsychiatric symptoms severity and impact on

caregivers; dyads’ anxiety, depression and attachment

style). Finally, we looked at possible explanatory factors

of QOL, including socio-demographic factors as well as

the degree of severity of the cognitive impairment.

RESULTS

Study population

Of the 730 subjects screened in the 7 Memory Clinics

(Figure 1), 148 (74 patient-caregiver dyads) were

enrolled into the study. After excluding subjects varying

more than 2 standard deviation from the mean in their

WHOQOL total TSF score between t0 and t0’, 127

subjects (85.81%; 66 patients and 61 caregivers) entered

baseline analyses; 105 (70.95%; 54 patients and 51

caregivers) completed the 6 months follow-up, and 98

(66.22%; 50 patients and 48 caregivers) completed the

12 months assessment. Total rate of dropout was

33.78%. Losses to follow-up are described in Figure 1.

Sociodemographic characteristics of the study

population and patients’ clinical profile are described in

Tables 1 and 2, respectively. Patients were aged 65-90

years (mean ± S.E.M. = 76.30 ± 0.84 years), 47% of

them were women and 59.1% had a diploma higher than

primary qualifications. Mean Montreal Cognitive

Assessment (MoCA) score at t0’ was 20.02 ± 0.52

(S.E.M.) (that is, an equivalent MMSE of 26) and most

patients were diagnosed with MCI (60.6%), principally

due to neurodegenerative diseases (80.3%, of which

66.7% Alzheimer’s disease. Note that patients may

receive a mixed diagnosis (e.g., a neurodegenerative

disease coupled with a vascular disease). Over half of

the patients (56.1%) had partial or absent awareness of

cognitive deficits (i.e., anosognosia).

Caregivers were aged 43-87 years (mean ± S.E.M. =

69.6 ±1.4 years), 65.6% of them were female, 77% had

a diploma higher than primary qualifications and 32.8%

still had a professional activity. The large majority of

caregivers lived with the patient (94.3%) and were their

life-partner (77%).

Baseline: reliability of the WHOQOL instrument

We looked at the WHOQOL TSF total mean score for

both patients and caregivers at t0 and t0’ in order to

assess the reliability of the instrument in the absence

of intervention. Patients’ WHOQOL total mean score

was 75.46% ± 1.24% at t0 and 76.22% ± 1.22% at

t0’. Caregivers’ WHOQOL total mean score was

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76.81% ± 1.19% at t0 and 75.84% ± 1.03% at t0’.

Paired-sample t-tests showed no significant difference

over baseline, neither in patients (t65 = -1.41; p = 0.16),

nor in caregivers (t60 = 1.53; p = 0.13). In conclusion,

the WHOQOL instrument was reliable for the patients

and caregivers reported in the analysis.

Patients

Table 3 presents patients’ mean scores (± S.E.M.) at t0’,

t1 and t2. The experimental group (i.e., ≥2NDIs)

included 63% patients at t1 and 64% patients at t2.

Solely statistically significant results are reported.

Influence of NDIs on QOL and other assessment tools

The 2x2 ANOVAs on WHOQOL scores revealed a

main effect of session (F2,52 = 5.66; p ≤ 0.05) over the

t0’-t1 time period, and no significant effect over the t1-

t2 time period. That is, patients’ WHOQOL total score

increased significantly between t0’ and t1 (t53 = -2.38; p

≤ 0.05), independently of the NDI group but remained

stable between t1 and t2.

The influence of NDI number and type on WHOQOL

score was assessed by means of Pearson. The analysis

indicated a positive association between the evolution

of WHOQOL score and the number of medico-social

NDIs between t0’ and t1 (r52 = 0.35; p ≤ 0.05) and a

negative association between t1 and t2 (r48 = -0.31;

p ≤ 0.05). That is, QOL increased with a higher number

of medico-social NDIs over the first 6 months and it

decreased over the 6-12 months period.

The 2x2 ANOVAs on other assessment tool scores

revealed that patients in the experimental group had

higher depression scores (main effect of NDI group on

HAD-D: F2,52 = 4.03; p ≤ 0.05; post-hoc: t53 = -2.01;

p ≤ 0.05) and lower MoCA score (main effect of NDI

group: F2,52 = 9.58; p ≤ 0.05; post-hoc: t53 = 3.10;

p ≤0.05) than the control group between t0’ and t1. The

2x2 ANOVA conducted on DAD-6 over the t0’-t1

period revealed a main effect of session (F2,52 = 7.18;

p ≤ 0.05), a main effect of NDI group (F2,52 = 6.29;

p ≤ 0.05), and a significant session*NDI group

interaction (F2,52 =10.16; p ≤ 0.05). That is, patients in

the experimental group were less functionally

autonomous (t53 = -2.51; p ≤ 0.05), irrespective of the

session (i.e., t0’ or t1). Further, functional autonomy

decreased significantly for the experimental group

between t0’ and t1 (t53 = 4.82; p ≤ 0.05) and the NDI

groups had reached significantly different scores at t1

(t53=3.52; p≤0.05). However, all patients decreased in

functional autonomy over the first 6 months,

independently of the NDI group (t53 = -2.68; p ≤ 0.05).

Figure 1. Flowchart of participants.

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Table 1. Sociodemographic characteristics of patients and their caregivers at t0’.

Patients Caregivers

Participants (n) 66 61

Age

Mean±SEM in years 76.3 ±0.8 69.6 ±1.4

Sex

Women 47% 65.6%

Men 53% 34.4%

Relationship

Partner 80.3%

Child 14.8%

Family 3.2%

Friend 1.6%

Education level

Primary school 40.9% 23%

Secondary school 33.3% 36%

Higher education 25.8% 41%

Caregiver Employment status

Employed 32.8%

Unemployed 67.2%

SEM: standard error of the mean; n: sample size.

Table 2. Clinical characteristics of patients at t0’.

Patients (n) 66

MoCA

Mean±SEM 20.0±0.5

Diagnostic at inclusion

MCI 60.6%

Dementia (Mild, CDR=1) 39.4%

Disease Etiology

Neurodegenerative 80.3%

AD 66.7%

LBD 4.5%

PPA 1.5%

FTD 1.5%

Other 9.1%

Vascular 36.4%

Thymic 12.1%

Toxic 13.6%

Other 21.2%

Nosognosia

Absent 16.7%

Partial 39.4%

Fully present 43.9%

SEM: standard error of the mean; MoCA: Montreal cognitive assessment; MCI: Mild cognitive impairment; CDR: Clinical dementia rate; AD: Alzheimer's disease; LBD: Lewy-body dementia; PPA: Primary progressive aphasia; FTD: Fronto-temporal dementia.

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Table 3. Patients: mean scores of questionnaires across follow-up sessions.

Time point t0’ t1 (6months) t2 (12 months)

Patients (n) 66 54 50

Questionnaires (scores in mean ± SEM)

WHOQOL (in %) 76.22 ± 1.22 77.43 ± 1.30 76.62 ± 1.49

MoCA (in ratio obtained/tested) 0.67 ± 0.02 0.67 ± 0.02 0.66 ± 0.02

QPC 2.83 ± 0.23 2.52 ± 0.24 2.35 ± 0.22

HAD

Anxiety 5.20 ± 0.46 5.04 ± 0.46 5.53± 0.50

Depression 3.98 ± 0.38 3.78 ± 0.39 3.96 ± 0.39

Fried Frailty 1.28 ± 0.15 1.24 ± 0.15 1.20 ± 0.16

NPIQ (in ratio obtained/tested)

Severity 0.15 ± 0.02 0.14 ± 0.01 0.15± 0.01

Repercussion 0.10 ± 0.01 0.09 ± 0.01 0.10 ± 0.01

DAD-6 (in ratio obtained/tested) 0.77 ± 0.03 0.68 ± 0.04 0.65 ± 0.04

Katz Index 5.72 ± 0.08 5.76 ± 0.06 5.57 ± 0.10

CIRS-G 7.83 ± 0.55 7.88 ± 0.54 8.41 ± 0.59

RQ

Secure 74.07% - -

Preoccupied 18.52% - -

Dismissing 7.41% - -

Fearful 0.00% - -

Nosognosia

Absent 16.66% 16.66% 22.00%

Partial 39.40% 48.15% 32.00%

Fully present 43.94% 35.19% 46.00%

NDI type (n)

Functional - 25 28

Cognitive - 16 17

Medico-social - 14 16

Psychology - 30 31

Socialization - 9 10

SEM: standard error of the mean; MoCA: Montreal cognitive assessment; QPC: Questionnaire of Cognitive Complaints; HAD: Hospital Anxiety and Depression Scale; NPIQ: Neuropsychiatric Inventory Questionnaire; DAD-6: Disability Assessment for Dementia; CIRS-G: Modified Cumulative Illness Rating Scale for Geriatrics; RQ: Relationship Questionnaire; NDI: Non-drug intervention.

Between t1 and t2, patients in the experimental group

were functionally less autonomous than those in the

control group, irrespectively of the session (main effect

of NDI group: F2,48 = 6.71; p ≤ 0.05; post-hoc: t49 = 2.59;

p ≤ 0.05).

Evolution of other assessment tools and association

with QOL, independently of NDI group Statistical analyses conducted over t0’-t1 and t1-t2 time

periods on DAD-6 scores revealed a significant

decrease in functional autonomy in patients between

t0’and t1 (t53 = 3.20; p ≤ 0.05). The analyses also

showed a loss of autonomy in daily basic activities (i.e.,

ADL) between t1 and t2 (t49 = 2.13; p ≤ 0.05).

Pearson tests over the t0’-t1 period revealed negative

correlations between the variation of scores of

WHOQOL and scores of HAD-anxiety (r52 = -0.33;

p ≤ 0.05) and NPIQ-severity (r52 = -0.27; p ≤ 0.05).

That is, increased anxiety traits and neuro-psychiatric

symptoms’ severity were associated with a decreased

QOL.

Factors influencing the evolution of QOL

In patients, ANOVAs on WHOQOL scores revealed a

main effect of gender over t0’-t1 (F2,52 = 6.83; p ≤ 0.05)

and t1-t2 (F2,48 = 5.92; p ≤ 0.05). Post-hoc showed that

women patients had a higher QOL than men, over

both t0’-t1 (t53 = 2.61; p ≤ 0.05) and t1-t2 (t49 = 2.43;

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Table 4. Caregivers: mean scores of questionnaires across follow-up sessions.

Time point t0’ t1 (6months) t2 (12 months)

Caregivers (n) 61 51 48

Questionnaires (scores in mean ± SEM)

WHOQOL (in %) 75.84 ± 1.03 74.33 ± 1.54 73.01 ± 1.48

PHQ-15 5.75 ± 0.42 5.96 ± 0.52 6.04 ± 0.53

Zarit (in ratio obtained/tested) 0.23 ± 0.02 0.25 ± 0.02 0.26 ± 0.02

HAD

Anxiety 7.24 ± 0.55 7.41 ± 0.56 7.85 ± 0.60

Depression 2.98 ± 0.33 3.59 ± 0.40 3.69 ± 0.39

RQ

Secure 76.47% - -

Preoccupied 13.73% - -

Dismissing 5.88% - -

Fearful 3.92% - -

NDI type (n)

Functional - 0 0

Cognitive - 0 0

Medico-social - 2 2

Psychology - 11 12

Socialization - 0 0

SEM: standard error of the mean; PHQ-15: Patient Health Questionnaire; Zarit: Zarit Burden Interview; HAD: Hospital Anxiety and Depression Scale; RQ: Relationship Questionnaire; NDI: Non-drug intervention.

p ≤ 0.05) time windows. The ANCOVAs revealed a main

effect of age over both t0’-t1 (F2,52 = 7.08; p ≤ 0.05) and

t1-t2 (F2,48 = 4.71; p ≤ 0.05) time periods. Post-hoc

Pearson correlations showed negative associations

between QOL and age at t0’ (r64 = -0.39; p ≤ 0.05), t1

(r52 = -0.39; p ≤ 0.05) and t2 (r48 = -0.27; p ≤ 0.05). That

is, female and younger patients had a higher QOL,

irrespective of time session.

ANOVAs analysis revealed session*activity (F2,52 =

9.58; p ≤ 0.05) and session*financial care (F2,52 = 4.24;

p ≤ 0.05) interactions between t0’ and t1. Post-hoc

t-tests revealed that patients’ QOL significantly

increased between t0’-t1 when the caregiver did not

work (t53 = -3.90; p ≤ 0.05) and when the caregiver did

not provide financial care (t53 = -3.07; p ≤ 0.05).

Finally, patients’ severity of cognitive impairment (i.e.,

MCI vs. dementia and patients’ MoCA score) and

functional autonomy (DAD6 and ADL) showed no

influence on patients’ QOL (pval > 0.05).

Continuity of the NDIs beyond 6 months

The 1-way ANCOVA conducted on the WHOQOL

total score (t1;t2) with the covariate of ratio “NDI

stopped after t1 / NDI started at t0’” revealed a main

effect of ratio (F2,48 = 6.74; p ≤ 0.05). Post-hoc Pearson

correlation tests showed a negative association between

QOL at t2 and the ratio (r48 = -0.36; p ≤ 0.05). That is,

the higher the number of NDIs stopped between t1 and

t2, the lower the QOL at t2.

Caregivers: quality of life, NDIs, influencing factors

Table 4 presents caregivers’ mean scores (±S.E.M.) at

t0’, t1 and t2. The experimental group (i.e., ≥2NDIs)

included 58.8% caregivers at t1 and 60.4% at t2. Solely

statistically significant results are reported.

Influence of NDIs on QOL and other assessment tools The 2x2 ANOVAs on WHOQOL scores revealed no

significant effect. That is, caregivers’ QOL remained

stable over both t0’-t1 and t1-t2 time intervals and in

both NDI groups (experimental and control).

The influence NDI number and type on WHOQOL

score was assessed by means of Pearson and showed no

significant results. That is, number and type of NDIs did

not influence caregivers’ QOL over the 12 months of

assessment.

The 2x2 ANOVAs on burden assessment tool Zarit

over t0’-t1 revealed a main effect of NDI group (F2,49 =

5.73; p ≤ 0.05) and a session*NDI group interaction

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(F2,49 = 6.12; p ≤ 0.05). The same analysis conducted over

t1-t2 revealed a main effect of NDI group (F2,46 = 7.67;

p ≤ 0.05). That is, caregivers in the experimental group

were more burdened than the control group between

t0’-t1 (t50 = -2.39; p ≤ 0.05) and t1-t2 (t47 = -2.77;

p ≤ 0.05). Also, caregivers in the experimental group had

a significant increase of their burden feeling between

t0’ and t1 (t50 = -3.00; p ≤ 0.05) and, at t1, their burden

was significantly higher than controls (t50 = -3.04;

p ≤ 0.05).

Finally, the 2x2 ANOVAs conducted on the HAD-

depression scale between t0’and t1 showed a

session*NDI group interaction (F2,49 = 4.73; p ≤ 0.05).

Post-hoc analyses revealed that caregivers in the

experimental group had significantly increased

depression traits over the first 6 months (t50 = -2.83;

p ≤ 0.05).

Evolution of other assessment tools and association

with QOL, independently of NDI group Statistical analyses conducted over t0’-t1 and t1-t2 time

periods showed no significant changes in the

assessment tools, independently of the NDIs.

When investigating whether the evolution of QOL was

associated with the evolution of other assessment tools

over the t0’-t1 time period, Pearson tests revealed

negative correlation between difference (t1-t0’) scores

of WHOQOL and HAD-anxiety (r49 = -0.60; p ≤ 0.05),

HAD-depression (r49 = -0.58; p ≤ 0.05), Zarit (r49 = -

0.42; p ≤ 0.05), and PHQ-15 (r49 = -0.37; p ≤ 0.05). That

is, a decrease in QOL between t0’ and t1 was associated

with increasing anxiety and depression traits, increased

burden perception and more physical health issues.

Over the t1-t2 time period, Pearson correlation tests

revealed negative associations between WHOQOL and

HAD-anxiety (r46 = -0.50; p ≤ 0.05) and Zarit (r46 = -0.38;

p ≤ 0.05). That is, a decrease in QOL between t1 and t2

was associated with increased anxiety and burden traits.

Factors influencing the evolution of QOL ANOVAs revealed a main effect of professional activity

over t0’-t1 (F2,49 = 6.99; p ≤ 0.05) and t1-t2 (F2,46 = 5.51;

p ≤ 0.05). Post-hoc showed that working caregivers had

a higher QOL than those who did not work over both

first (t50 = -2.64; p ≤ 0.05) and second (t47 = -2.35;

p ≤ 0.05) time intervals.

ANOVA conducted over t0’-t1 revealed a main effect

of patient’s diagnosis (i.e., MCI vs. dementia) (F2,49 =

4.06; p ≤ 0.05). Post-hoc showed that caregivers looking

after patients diagnosed with dementia (vs. MCI) had a

significantly lower QOL (t50 = -2.02; p ≤ 0.05),

independently of the session.

ANOVA conducted over t1-t2 revealed a main effect of

gender (F2,46 = 4.79; p ≤ 0.05). Post-hoc analyses

showed that women caregivers had a significantly lower

QOL than men (t47 = 2.19; p ≤ 0.05), independently of

the session.

Finally, patients’ severity of cognitive impairment (i.e.,

MCI vs. dementia and patients’ MoCA score),

functional autonomy (DAD6 and ADL) and nosognosia

level (i.e., present, partial, absent) showed no influence

on caregivers’ QOL (pval > 0.05).

Continuity of the NDIs beyond 6months In caregivers, the 1-way ANCOVA conducted on the

WHOQOL total score (t1;t2) with the covariate of ratio

“NDI stopped after t1 / NDI started at t0’” revealed a

main effect of ratio (F2,46 = 21.40; p ≤ 0.01). Post-hoc

Pearson correlation tests showed a negative association

between QOL at t2 and the ratio (r46 = -0.55; p ≤ 0.05).

That is, the higher the number of NDIs stopped between

t1 and t2, the lower the QOL at t2.

Further, the 1-way ANCOVAs conducted with the

covariate of ratio “NDI stopped after t1 / NDI started at

t0’” revealed a main effect of ratio when computed with

the scores of HAD-depression (F2,46 = 13.8; p ≤ 0.01),

HAD-anxiety (F2,46 = 17.1; p ≤ 0.01) and PHQ-15 (F2,46 =

9.95; p ≤0.05). Post-hoc Pearson correlation tests showed

a positive association between the ratio of stopped NDIs

and HAD-depression (r46 = 0.45; p ≤ 0.01), HAD-anxiety

(r46 = 0.54; p ≤ 0.01) and PHQ-15 (r46 = -0.35; p ≤ 0.05).

That is, an increased ratio of NDIs stopped at t1 was

associated with increased anxiety and depression traits, as

well as increased physical health issues at t2.

DISCUSSION

Effect of NDIs on patients’ and caregivers’ QOL

Our results show that caregivers’ QOL is especially

associated to their own health (e.g., anxiety, depressive

and physical symptoms) and burden perception, rather

than to patient’s attributes (e.g., neuropsychiatric and

behavioral symptoms [11, 12]). This opens the door to

guidelines on how to provide caregivers with coping

strategies aimed at successfully deal with their new role

and associated burden.

Quality of life increased within the first 6 months of

intervention in patients and remained stable 6 months

later. The initial increase of QOL was independent of

the number of NDIs implemented. The absence of effect

of multiple intervention over a single one may reflect

the similar attention and care that both groups of dyads

received as early as their first session of the study

research.

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The evolution of QOL in patients was inversely

associated with their own anxiety and severity of

neuropsychiatric symptoms. These observations concur

with previous results showing negative associations

between patient’s QOL and anxiety in both persons with

[11] and without dementia [31], as well as between

patient’s QOL and the presence of neuropsychiatric

symptoms [11, 16]. It has been suggested that anxiety

symptoms could represent a prodromal stage of

depression, or even a vulnerability to develop it [32].

Among all the dementia’s neuropsychiatric symptoms,

depression is one of the most frequently observed in

MCI and early stage of AD [33] and MCI patients have

a double risk of developing AD when depression is

present [34]. In this study, more depressed, more

cognitively affected and less autonomous patients were

those who received a combination of multiple NDIs,

confirming that the attribution of NDIs in the different

Memory Clinics has been done on a clinical basis

according to patients’ needs.

On the caregivers’ side, QOL was stable throughout the

year of assessment and was associated within the first 6

months to their own anxiety and depression, physical

symptoms and burden perception. Previous findings

similarly highlight significant inverse associations

between depression and both caregivers’ [35] and

patients’ [36] QOL, while others show that caregivers’

depression could serve as a predictor of their burden [37],

thus suggesting the importance of early identification of

depressive symptoms not only in patients with cognitive

decline but also in their caregivers.

Factors influencing QOL

We found four socio-demographic variables that

influenced patients’ QOL.

First, being a male patient was found to be associated

with a worse QOL. Traditionally, the concept of men

being the head of households was highly recurrent and

still true for the generation of our patients. In this view,

we suppose that when male patients experience the

difficulties engendered by cognitive decline, they may

feel embarrassed to delegate tasks that they previously

fully handled (e.g., financials). Second, we found that

the older the patient, the lower the QOL. This is in

contrast with a study on cognitively affected patients,

which observed an increased QOL with ageing [11].

However, patients were more cognitively affected than

in our study. Third, patients’ QOL increased over the

first 6 months when the caregiver was not working and

was not responsible for the financial affairs of the

patient; however, this effect disappeared later on. We

suspect that at the beginning of interventions patients

appreciate a caregiver who is more present to help with

the organization of the different therapy appointments.

Finally, the preservation of one’s financial affairs

management appears to be important for patients’ self-

esteem, at least at the beginning of the disease. We did

not highlight any significant difference in MCI

compared to mild dementia patients’ QOL. Previous

studies in more severely patients also failed to show

QOL variations with dementia progression [38, 39].

This suggests that the progression of cognitive deficits

does not necessarily affect patients’ QOL.

In caregivers, three main socio-demographic variables

had a significant effect on QOL.

First, in our study, male caregivers have a better QOL

than females. In line with this result, QOL literature

reports that women caregivers show significantly

inferior QOL than men [22, 23]. This fact has been

referred to differences in coping strategies. Generally, it

is admitted that men focus on practical tasks, confront

the problem and are able to create a psychological

distance with the patient [40]. Women instead usually

prefer emotion-focused strategies and emotional support

is often accompanied by worrying, sorrow and self-

accusation [41], all of which have been associated to

burden and anxiety [42].

Second, QOL of caregivers engaged in a professional

activity was higher. In line with our result, other studies

reported inverse associations between caregiver’s

occupational status and depression [43], as well as

delayed patients’ institutionalization when caregiver

was in good health and spent less time providing care to

the patient [28, 29]. Maintaining a professional activity

appears therefore to be a protective factor for caregivers

against excessive burden for patient’s care. In addition,

being engaged in something other than the care of the

patient allows caregivers to favor social relationships

and obtain personal sources of satisfaction, all important

determinants of QOL. However, whether caregivers

express the need to maintain their professional activity,

patients judge their QOL higher when the caregiver

does not work. This should serve as a warning sign

for therapists, who need to appreciate whether the dyad

has found the appropriate compromise between assuring

the presence of the caregiver to the patient while

avoiding that this new role does not repress the

caregiver.

Lastly, caring to an MCI patient rather than a patient

suffering of a mild dementia is associated to a better

QOL within the first 6 months of intervention. We

suppose that caregivers of MCI patients who by

definition have a spared functional autonomy, need to

spend less time taking care of their patient and for that

reason report a better QOL.

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Finally, we found of high interest that whereas patients’

cognitive status does not influence the QOL of our

dyads, many socio-demographic factors do so. This

finding encourages the employment of interventions

that should not exclusively focus on the disease itself,

but rather target individual characteristics.

Number, type and long-term continuity of NDIs

The results could not highlight a difference in the effect

of a combination of interventions against the effect of a

single intervention. Interestingly, we found that the only

intervention type showing a significant impact on QOL

is the medico-social. As a reminder, medico-social

interventions include social assistant support, nurse

home assistance, community health centers and expert

unit for old age-related issues. The results show that the

more of medico-social interventions the patients had

(namely different interventions of the same type), the

better was their QOL 6 months later. However, when

these same interventions were still present between 6

and 12 months, their QOL diminished. This should

question about patients’ perception of medico-social

interventions. In particular, patients appreciate a reduced

turnover of the nurses that are visiting them at home.

On the other side, we highlight that continuing NDIs on

the long-term might be important for maintaining QOL

beyond 6 months. Indeed, NDIs are often offered in the

form of fixed number of sessions and we clinically

observed in the present study that several therapies were

only pursued during the first 6 months and then

interrupted for various reasons (in particular,

insufficient insurance coverage or unrenewed doctor

referrals). However, cognitive impairment in dementia

aggravates continuously and the need for interventions

is therefore still applicable. Here, we found that the

more interventions were stopped after 6 months, the

lower the QOL was rated at the end of the study, in both

patients and caregivers. In addition, it appears that

interrupting NDIs prematurely is not only detrimental

for QOL but for other measures as well. In particular,

the ratio of interrupted interventions was associated

with more caregivers’ anxiety and depressive traits and

increased physical health problems 6 months later. This

also highly threaten caregivers’ burden. Finally,

changes in QOL were not due to patients’ progressive

cognitive decline or reduced functional autonomy in

this study, as we failed to find any significant

correlation between these measures and dyads QOL.

This reduces the possibility that interruption of NDIs

was a consequence - and not a source - of QOL

decrease. These results must nevertheless to be

considered with caution, as we cannot completely

exclude that other factors may influence the premature

interruption of an intervention.

On the light of these results, clinicians should consider

to pursuing interventions for a better maintain of

patients’ QOL. Nonetheless, they should also pay

attention to the modality of these interventions, with a

particular consideration on patient’s wishes and needs.

CONCLUSIONS AND CLINICAL

IMPLICATIONS

In order to adequately respond to the increasing aging

population and the rising number of patients with

dementia, we need to obtain better knowledge of the

needs of the patients as well as of his main caregiver.

We aimed here at taking a closer look at how NDIs are

implemented in memory centers to face the decline in

patient’s functional autonomy and maintain QOL. We

highlight that QOL is a complex concept and identified

specific factors that may influence QOL in patients but

also in caregivers. Interestingly, we found that the

number or type of NDIs is not determinant; however,

adapted interventions should be maintained in a long-

term follow-up to be beneficial, or, alternatively, a

continuity within associative activities to maintain the

NDIs’ benefice should be organized.

Limitations

The study has some limitations. The sample size was

lower than what initially targeted, and this necessarily

contributed to weaken the statistical power of our study.

Also, the limited sample size did not allow us to conduct

subgroups analysis to exclude all confounders. For

ethical and clinical reasons, our trial design did not

include randomization and is therefore exposed to a

selection bias (patients suffering from more severe

cognitive troubles need more than one NDI). Further,

concerned by offering patients and their caregiver the

best personalized intervention option, we intentionally

chose not to include a group with no intervention. Indeed,

our clinical experience showed that an overall refusal of

proposed intervention is extremely rare in the context of

patients’ consultation at the Memory Clinics and we did

not want to deprive dyads from possible intervention.

Moreover, we assumed that a dyad who would refuse all

proposed NDI would also be very likely to refuse its

enrolment in a clinical study. Another limitation is that

the results of the study might not be applicable to patients

with more severe dementia, which were indeed excluded

from the study as our questionnaires require good

comprehension skills to be completed. Finally, regarding

the effect of interventions, we cannot rule out the

possibility that the one-to-one contact with the research

assistant of the study represents an implicit intervention

itself. Actually, at each time session, the dyads had a

space where discuss about their personal experience of

the progressive disease and the difficulties they meet.

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MATERIALS AND METHODS

Study population and sample size

Patients with cognitive impairment and their caregivers

were recruited between April 2017 and August 2018 in

7 Memory Clinics of the French-speaking part of

Switzerland. Patients and their main caregivers were

seen in a Clinic and the study was proposed according

to diagnosis and if one or more NDI was recommended.

The choice of adapted NDIs was based on the

multidisciplinary assessment performed in each

memory clinic (in particular by a neurologist,

psychiatrist, geriatrician and/or neuropsychologist). In

addition, liaison nurse or social assistant also

investigated patients’ and caregivers’ needs and

preferences for particular activities or interests to

propose the dyad the most personalized and adapted

intervention as possible. The aims, costs/benefits and

procedure of the study were explained to the dyad

(patient-caregiver), which then received the study

information, protocol and informed consents for a 7-day

reflection. All patients and caregivers willing to

participate were invited for the first interview with the

research assistant to sign the informed consent to

participate in the study and to fill up a demographic

questionnaire. The criteria for patients’ inclusion were:

age 65 or older; capable of consent; diagnosis of Mild

Cognitive Impairment (MCI) or dementia (Clinical

Dementia Rating Score [44] of maximum 1); no major

psychiatric disease; no NDI(s) already implemented and

an existing caregiver. Caregivers’ inclusion criteria

were: age 18 years and over; capable of consent; no

major psychiatric disease. All included participants

signed the informed consent. The study was approved

by the cantonal ethics committee on human research of

canton de Vaud (CER-VD).

The sample size was calculated based on a previous

study with aged patients (>65) and similar expected

outcome (WHOQOL) in participants [45]. We aimed at

including 100 subjects in each group to reach a

statistical power of 80% and demonstrate a difference in

QOL with a 0.05 alpha (two-sided). To ensure an

adequate number of samples, we planned to screen 300

subjects.

Measures

Socio-demographic status A demographic and background information

questionnaire was used to collect information on dyads’

socio-demographic characteristics (e.g. age, gender,

level education, working status, duration of relationship

with caregiver) as well as patients’ clinical data

(diagnosis, etiology).

Quality of life Quality of life was measured using the WHOQOL-OLD

and BREF questionnaires. The WHOQOL-OLD is a 24-

item measure of QOL developed by the WHOQOL

Group [46] as an add-on module to their already existing

QOL measures (WHOQOL-100 [47] and WHOQOL-

BREF [48]). It has been specifically designed for use

with older adults. Items address six facets: sensory

abilities; autonomy; past, present and future activities;

social participation; death and dying; intimacy. Each of

the facets consists in four items, rated on a five-point

Likert scale. High scores represent high QOL and low

scores represent low QOL. The WHOQOL-BREF is a

26-item version of the WHOQOL-100 assessment. We

used it to assess younger caregivers’ QOL (<60 years

old) throughout 4 QOL domains: physical health,

psychological, social and environmental. The instrument

was previously demonstrated as having good to excellent

psychometric properties [48]. The WHOQOL-BREF and

–OLD were self-administered when possible.

Cognitive impairment, physical health and autonomy

Patient’s cognitive impairment was assessed using the

Montreal Cognitive Assessment (MoCA) [49] versions

1, 2 and 3 alternatively (i.e. to avoid repetition effect),

whereas stage of physical frailty was determined with

the Fried frailty phenotype method [50]. Both MoCA

and Fried tools were administered by the research

coordinator. The patients’ functional autonomy and

ability to perform basic and instrumental activities of

daily living (ADL) was measured, respectively, with the

Katz’s Index of Independence in ADL [51] and the

Disability Assessment for Dementia scale (DAD6) [52].

These two scales were completed according to the

caregiver’s opinion. The Modified Cumulative Illness

Rating Scale for Geriatrics (CIRS-G) [53] was used to

highlight patients’ chronic medical illness burden and

was filled-up by doctors or nurses from the Memory

Clinic. Caregiver’s physical symptoms were self-

assessed with the Patient Health Questionnaire (PH-

Q15) [54].

Psychological status Patients’ neuropsychiatric symptoms severity and impact

on caregivers were identified with the Neuropsychiatric

Inventory scale (NPI-Q) [55], as reported by the

caregiver. Anxiety and depression of patients and

caregivers were measured using the Hospital Anxiety and

Depression Scale (HADS) [56] as self-assessment.

Patients’ and caregivers’ attachment style was self-

determined with the Relationship Questionnaire (RQ)

[57], which distinguishes 4 different adult attachments:

secure (positive view of self and others), preoccupied

(negative view of self but a positive view of others),

dismissing (positive view of self and negative view of

others), and fearful (negative view of self and other). The

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caregivers self-reported their feeling of burden using the

Zarit Burden Interview. Finally, patients’ awareness of

their cognitive impairment (i.e. nosognosia) was

determined according to concordance between patients’

complaints of cognitive impairment and neurologists’

and/or neuropsychologists’ assessment; in addition, the

Questionnaire of Cognitive Complaints (QPC for the

French version of the questionnaire) was used to measure

subjective cognitive complaints with questions assessing

the presence of cognitive difficulties in the last six

months [58].

Study design

INDID-MCI-QOL is a longitudinal, quasi-experimental

and multicenter study coordinated by the Centre

Leenaards de la Mémoire of the university Hospital in

Lausanne (CHUV). Patients and caregivers were seen 4

times over a 12.5 months follow-up period by the same

research collaborator within their Memory Clinic. These

meetings took place in one of the 7 Memory Clinics or

at the dyad’s home upon request. Dyads consistently

met the research collaborator from their region who

administered the assessment tools. Dyads were

encouraged to fill up the questionnaires individually to

allow for more privacy and freedom of speech. When

requested by one of the participants, dyads were

allowed to stay together during the assessment.

At t0, information and consent form were signed by

both patients and caregivers. The dyad also completed

individually the demographic and background

information questionnaire, as well as the WHOQOL

questionnaire for a first measure of QOL. Two weeks

later (t0’), QOL was measured again to assess its

stability in the absence of NDI(s) (i.e. QOL baseline). In

addition, a set of baseline measures were acquired

before the beginning of NDIs. Non-drug interventions

were then implemented, and subjects’ follow-up visits

were planned at 6 (t1) and 12 (t2) months after t0’. To

ensure a thorough follow-up, all questionnaires of both

patients and caregivers were completed at the 3 time

points (t0’, t1 and t2), only the RQ was exclusively

administered once at t0’ due to the known stability of

adult attachment throughout life [59].

According to the number of NDIs accepted by the

patient and his caregiver, the dyads were classified into

two different groups: “Experimental” (≥2 NDIs) and

“Control” (1 NDI). Dyads who switched from 1NDI to

≥2 NDIs between t1 and t2 were considered as

“Control” for t1 statistical analyses and “Experimental”

for t2 statistical analyses. Dyads who switched from ≥2

NDIs to 1NDI between t1 and t2 were kept in the

“Experimental” group since strategies implemented

with the intervention that has been stopped might still

be on use. Due to both ethical and practical reasons, no

group “without” NDI was included.

Interventions

For study simplification, NDIs were empirically

subdivided into 5 categories: functional, cognitive,

medico-social, psychology and socialization. Functional

interventions included therapies such as ergotherapy,

physiotherapy and other physical activities. Cognitive

interventions consisted of interventions such as

neuropsychology, speech therapy or memory workshops.

Medico-social interventions comprised social assistant

supports, nurse home assistance, community health

centers and an expert unit for old age-related issues (Pro

Senectute ®). Psychologic interventions included

patients’ or caregivers’ psychotherapy, support group, art

therapy. Finally, social interventions proposed social

activities as well as day care center for patients.

Outcomes

The primary outcome was the effect of multiple and

personalized NDIs on patients’ and caregivers’ QOL as

measured by the WHOQOL instruments. We

investigated whether a combination of multiple

implemented NDIs led to higher WHOQOL scores (i.e.,

better QOL) than single interventions. Secondary

outcomes included the effect of NDIs on the other

measured instruments (i.e., assessing patients’ cognitive

impairment, physical frailty, functional autonomy and

chronic medical illness burden; caregivers’ physical

symptoms and burden; patient’s neuropsychiatric

symptoms severity and impact on caregivers; dyads’

anxiety, depression and attachment style) as well as the

associations between them. We also assessed how

socio-demographical factors as well as the degree of

severity of the cognitive impairment influenced the

evolution of QOL over a 12 months period,

independently of the implemented NDIs. Finally, we

investigated the importance of the continuity of NDIs

for the evolution of QOL.

Statistical analyses

As previously approved by the cantonal ethics

committee on human research of canton de Vaud (CER-

VD), participants’ scores were collected and recorded

using REDCap [60, 61] by the research collaborators of

the 7 Memory Clinics. This platform ensures data

security and anonymization. As patients and caregivers

were provided with different questionnaires, statistical

analyses were conducted separately for patients and

caregivers. Participants’ scores were calculated

according to the official guidelines of the assessment

tools.

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The WHOQOL (-OLD/-BREF) score was first

transformed into raw facet score (RFS) by summing the

items belonging to a facet. Then, a transformed facet

score (TFS), allowing to interpret scores in percent with

0 being the lowest and 100 the highest possible value,

was obtained for each subscale. The total score of the

WHOQOL(-OLD/-BREF) was calculated by summing

all the TFS scores of the individual subscales [62].

When a participant failed to answer one or more

questions, the subscale TFS score was recalculated

accordingly to obtain a correct total TFS score. In

caregivers, WHOQOL-OLD and WHOQOL-BREF

total TFS scores were pooled together.

As some participants failed to answer every question of

some assessment tools, a ratio “obtained score/tested

score” was created for the following scales: MoCA,

DAD-6, NPIQ (severity and repercussion) and Zarit.

This total ratio score accounts for between-participants’

discrepancies and further allows direct comparison and

statistical analyses.

All subsequent statistical analyses have been conducted

using the open source software “Jamovi, version 0.9”

[63] and P-Tukey corrections were applied when

appropriate to take into account multiple comparison

bias.

Baseline: stability of the QOL in the absence of NDI In order to assess the reliability of the WHOQOL

instrument in the absence of NDI, paired-sample t-tests

were conducted between the WHOQOL total TSF

scores of t0 and t0’ sessions within patients and within

caregivers.

To ensure that the effects observed in later analyses

were not due to some participants’ inconsistency,

individuals whose WHOQOL total score varied more

than 2 standard deviations from the mean (within

patients / caregivers separately) were excluded from

further analyses.

Evolution of the QOL and other assessment tools at 6

and 12 months as a function of NDIs

To increase statistical power by including as many

subjects as possible into statistical analyses, these latter

were conducted once over the t0’-t1 time window (i.e.

0-6months) and once over the t1-t2 time window (i.e. 6-

12months).

To assess whether NDI number had an impact on the

evolution of QOL over time, two-way ANOVAs were

conducted with the within factor of session (t0’ vs. t1 or

t1 vs. t2) and the between factor of NDI group (1 NDI

vs. ≥2 NDIs). Post-hoc paired t-tests were computed

when justified by the ANOVAs. Results were

considered significant when p ≤ 0.05. Identical analyses

were conducted to assess the effect of NDI group on the

other assessment tools (i.e. MoCA, QPC, HAD, Zarit,

NPIQ, Fried frailty, ADL, DAD-6, CIRS-G, PHQ-15).

Evolution of the QOL at 6 and 12 months as a

function of socio-demographical factors and of the

severity of the cognitive impairment To investigate how of socio-demographical or cognitive

categorical factors (e.g., gender, MCI/dementia)

influenced the evolution of QOL between t0’-t1 and t1-

t2, two-way ANOVAs were conducted with the within

factor of session (t0’ vs. t1 or t1 vs. t2). Post-hoc paired

t-tests were computed when justified by the ANOVAs.

Results were considered significant when p ≤ 0.05.

To assess the effect of socio-demographical or cognitive

continuous variable (e.g. age, MoCa score) influenced

QOL’s evolution, one-way ANCOVAs were conducted

with the within factor of session (t0’ vs. t1 or t1 vs. t2)

and the socio-demographical factor as covariate. Post-hoc

Pearson correlation tests were applied when appropriate.

Results were considered significant when p ≤ 0.05.

Evolution of other assessment tools

To assess how patients and caregivers performed in

other assessment tools (i.e. MoCA, QPC, HAD, Zarit,

NPIQ, Fried frailty, ADL, DAD-6, CIRS-G, PHQ-15)

over t0’-t1 and t1-t2 time windows, paired-sample t-

tests were conducted over these time windows,

independently of the NDI group. Results were

considered significant when p ≤ 0.05.

Co-evolution of the QOL and other assessment tools To investigate whether the evolution of QOL (i.e.

WHOQOL TSF total score) was associated with the

evolution of other assessment tools (e.g. HAD, Zarit,

NPIQ), linear regression was conducted by means of

Pearson correlation tests between t0’-t1 and t1-t2.

Results were considered significant when p ≤ 0.05.

Influence of the NDI type and number on the QOL Whether the number of each NDI category implemented

had an impact on QOL was assessed by means of linear

regression (Pearson correlation tests). That is, we

investigated whether the number of NDI within a

category (i.e. functional, cognitive, medico-social,

psychological, social) would differentially influence the

evolution of QOL (i.e. WHOQOL scores expressed in

differences: t1-t0’ or t2-t1). Results were considered

significant when p ≤ 0.05.

Effects of the continuity of NDIs beyond 6 months on

QOL and other assessment tools

Whether the continuity of NDIs beyond 6 months,

independently of their type or number, had an effect of

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QOL’s or any other assessment tool’s evolution was

assessed by:

1) Computing a ratio of NDIs stopped after 6

months/total NDIs started. This ratio NDI “stopped

after t1” / “started at t0’” was then used as a

covariate in a one-way ANCOVA with the within

factor of session (t1; t2) including scores of QOL or

other assessment tools. When justified by the

ANCOVA, post-hoc Pearson correlation tests were

applied. Results were considered significant when

p ≤ 0.05.

2) Computing binary variables describing the presence

or absence or NDIs between t1 and t2. That is, one

binary variable “had NDIs between t1-t2” (0 vs. 1)

and one variable “stopped at least one NDI between

t1-t2 (0 vs. 1), were computed. These variables were

then entered as between factors in one-way

ANOVAs including the within factor of session (t1;

t2) with the scores of QOL or other assessment tools.

When justified, post-hoc paired-sample t-tests were

conducted. Results were considered significant when

p ≤ 0.05.

Abbreviations

AD: Alzheimer’s disease; BPSD: Behavioral and

psychological symptoms of dementia; CDR: Clinical

dementia rate; CIRS-G: Modified Cumulative Illness

Rating Scale for Geriatrics; DAD-6: Disability

Assessment for Dementia; FTD: Fronto-temporal

dementia; HAD: Hospital Anxiety and Depression; LBD:

Lewy-body dementia; MCI: Mild cognitive impairment;

MMSE: Mini mental state evaluation; MoCA: Montreal

cognitive assessment; NDI: Non-drug intervention;

NPIQ: Neuropsychiatric inventory questionnaire; PHQ-

15: Patient Health Questionnaire; PPA: Primary

progressive aphasia; QOL: Quality of life; QPC:

Questionnaire of Cognitive Complaints; RFS: Raw facet

score; RQ: Relationship Questionnaire; SEM: Standard

error of the mean; TFS: Transformed facet score; WHO:

World Health Organization.

AUTHOR CONTRIBUTIONS

ABG: project conception; ABG, JFD, AVD, HM,

MHL, SP: study design; MLN, BLM: project

coordination, manuscript preparation; MLN, BLM,

CFC, MLM, MN, JG, MJT, GC: participant’s

screening, recruitment, questionnaire administration,

data collection; MLN: data analysis; MLN, BLM,

ABG, AVD, MHL, HM, SP, DD: data interpretation.

ABG, AVD, HM, MHL, SP: clinical advice. DD:

REDCap study implementation. All authors read and

approved the final manuscript.

ACKNOWLEDGMENTS

The authors thank all participants of the study and all

memory centers that actively collaborated to the study.

We especially thank Chantal Glassier, Nora Schneider

El Gueddari, Eloisa Brovedani, Françoise Colombo,

Jean-Marie Annoni, Oscar Daher, Rebecca Dreher,

Pierre Guillemin, Enver Lleshi, Giovanni Frisoni and

Jean-François Knebel. For the funding supported, we

thank the Leenaards and Floshield Foundations.

CONFLICTS OF INTEREST

The authors have no conflicts to declare.

FUNDING

This work was supported by the Leenaards and the

Floshield Foundations.

REFERENCES

1. World Health Organization. Dementia. 2019. www.who.int/news-room/fact-sheets/detail/dementia.

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